Currently some 200,000-cancer patients/year receive large field or WBI in the US. Approximately 20-50% of individuals surviving > 6 months will develop chronic progressive dementia than can lead to death. At the present time, there are no successful treatments for radiation-induced brain injury, nor are there any known effective preventive strategies. We propose to test the role of NADPH oxidase in acute and late radiation induced brain injury using a unique mouse transgenic model in which p47phox has been knocked out with the following Aims: 1. Determine the role of radiation in modulating NADPH oxidase in normal brain cells; 2. Determine the effect of NADPH oxidase inhibition on radiation-induced changes and re-dox regulated gene products in the brain endothelial cell; 3. Determine the role of NADPH oxidase in acute radiation-induced brain injury; 4. Determine the role of NADPH oxidase in chronic radiation-induced brain injury. If successful, these studies will be the first to demonstrate the role of NADPH oxidase in the chronic oxidative stress associated with radiation-induced brain injury and offer exciting novel interventional approaches. [unreadable] [unreadable]